Validation of an aneurysmal subarachnoid hemorrhage grading scale in 1532 consecutive patients.
The two most commonly used aneurysmal subarachnoid hemorrhage grading scales are the Hunt and Hess and World Federation of Neurological Societies scales. Neither has achieved universal acceptance, however, owing to concerns regarding either subjectivity or lack of correlation with outcomes, respectively. A grading scale based entirely on the Glasgow Coma Scale (GCS) was recently proposed. We have prospectively evaluated the GCS grading system and compared it with the Hunt and Hess and World Federation of Neurological Societies scales for predictive accuracy. Data from 1532 consecutive patients with intracranial aneurysms admitted to our institution between January 1991 and June 2005 were analyzed. The Glasgow Outcome Scale was the primary outcome measure. Mortality and length of stay were secondary measures. The scales were evaluated using simple and multivariable logistic and linear regression. Receiver operating characteristic curves were used to assess predictive accuracy for the Glasgow Outcome Scale. Prognostic factors were assessed with ordinal multivariable logistic regression. The GCS grading system was most strongly associated with all outcome measures and was the strongest predictor of mortality and persistent vegetative state. Age, vasospasm, hydrocephalus, and intracranial hematoma were found to be significant prognostic elements. The GCS grading system is more strongly associated with outcomes than either the Hunt and Hess or World Federation of Neurological Societies scales, and it is an equivalent to a slightly better predictor of Glasgow Outcome Scale outcomes. Its simplicity, proven inter-rater reliability, and wide level of familiarity among health care personnel render the GCS grading system a superior grading scale for aneurysmal subarachnoid hemorrhage severity, warranting its consideration for universal use.


Effect of chronic inhibition of angiotensin converting enzyme on baroreceptor reflex in essential hypertension.
We examined baroreflex function and plasma angiotensin II (Ang II) before and after the treatment with an angiotensin converting enzyme inhibitor (ACEI) in eight inpatients with essential hypertension (EHT). Baroreflex sensitivity (BS), expressed as a slope of linear relationship between %-changes in mean blood pressure (BP) and those in plasma concentration of norepinephrine (pNE), was greater during BP reduction by sodium nitroprusside (SNP) than during BP elevation by phenylephrine (PE). Enalapril treatment for 7 days reduced BP without a significant change in heart rate and pNE. It also increased the BS in two cases during SNP infusion and in four cases during PE infusion. Ang II was not significantly reduced after enalapril, while plasma ACE activity was suppressed by about 80% and plasma renin activity (PRA) was elevated. The changes in BS did not correlate with the changes in Ang II. The shift of barofunction curve with an enhancement of BS by enalapril therapy might not be attributed solely to the interaction between circulating Ang II and central baroreflex mechanisms.


Differential ability of colonial types of Neisseria gonorrhoeae to produce infection cutaneous perforated plastic chambers in guinea-pigs and rabbits.
Perforated plastic chambers implanted subcutaneously in guinea-pigs and rabbits became encapsulated and filled with sterile transudate. When these chambers in guinea-pigs were inoculated with various strans of Neisseria gonorrhoeae, persistent infections were achieved without the use of anti-inflammation agents and in the presence of a substantial predominantly polymorphonuclear inflammatory response. Two strains with small colonies similar to types 1 and 2, and one strain with large colonies similar to type 4 of Kellogg et al. (1963 and 1968), showed differences in infectivity comparable with those that might be expected in man, and passage through guinea-pig chambers increased this infectivity. Rabbit chambers could not be infected without the use of an anti-inflammation drug (betamethasone), and differences in infectivity between strains were not as clear cut. The growth of N. gonorrhoeae in chambers in the guinea-pig provides a convenient model system for studying some aspects of the pathogenicity of this organism.


Development and Characterization of a Neutralizing Anti-idiotype Antibody Against Mirvetuximab for Analysis of Clinical Samples.
Antibody-drug-conjugates (ADCs) are an emerging class of biological therapeutics. Mirvetuximab soravtansine is a novel folate receptor alpha (FRα)-targeting ADC which represents a potential new treatment for patients with ovarian and other FRα-positive cancers. Since patient immune responses to biological therapeutics may negatively affect drug efficacy and patient safety, regulatory authorities require rigorous monitoring of patient samples. Taking advantage of the immune system's ability to generate highly specific antibodies, the field has turned to anti-idiotype antibodies as powerful tools for the development of sensitive and specific bioassays. Here, we report the generation and characterization of a highly specific neutralizing anti-idiotype antibody directed against M9346A, the antibody moiety of mirvetuximab soravtansine. The anti-idiotype antibody recognizes M9346A with double-digit picomolar affinity, competes with folate receptor antigen for binding to M9346A, and can be used to develop both anti-drug-antibody and neutralizing antibody assays.


The association between stressful life events and breast cancer risk: a meta-analysis.
Breast cancer is the most prevalent cancer in women in Western societies. Studies examining the relationship between stressful life events and breast cancer risk have produced conflicting results. The purpose of this meta-analysis was to identify studies on this relationship, between 1966 and December 2002, to summarize and quantify the association and to explain the inconsistency in previous results. Summary odds ratios and standard errors were calculated, using random effect meta-regression analyses, for the following categories: stressful life events, death of spouse, death of relative or friend, personal health difficulties, nonpersonal health difficulties, change in marital status, change in financial status and change in environmental status. The presence of publication bias has been explored, and sensitivity analyses were performed to identify heterogeneity, using calculation of the percentage of variability due to heterogeneity, meta-regression analyses and stratification. Only the categories stressful life events (OR = 1.77, 95% CI 1.31-2.40), death of spouse (OR = 1.37, 95% CI 1.10-1.71) and death of relative or friend (OR = 1.35, 95% CI 1.09-1.68) showed a statistically significant effect. Publication bias was identified in both stressful life events (p = 0.00) and death of relative or friend (p = 0.02). Sensitivity analyses resulted in the identification of heterogeneity in all categories, except death of spouse. The results of this meta-analysis do not support an overall association between stressful life events and breast cancer risk. Only a modest association could be identified between death of spouse and breast cancer risk.


Should study subjects see their previous responses?
To test the relative merits of administering questionnaires with previous responses available (the informed condition) or unavailable (the blind condition), we administered blind and informed versions of a quality of life questionnaire to two groups of patients. One, a group of 43 stable subjects with chronic cardiorespiratory disease, were seen three times at fortnightly intervals; a separate series of 13 patients with chronic lung disease were evaluated before and after optimization of therapy. In the stable patients the informed strategy resulted in substantial decrease in the variance in the measurement of dyspnea, fatigue, and of emotional function. Large improvements in dyspnea, fatigue, and emotional function seen in patients undergoing treatment optimization were comparable using blind and informed methods. These results suggest that by letting patients see their previous responses we can decrease the sample size needed to detect changes in quality of life in clinical trials.


Response of red blood cell folate to intervention: implications for folate recommendations for the prevention of neural tube defects.
Committees worldwide have set almost identical folate recommendations for the prevention of the first occurrence of neural tube defects (NTDs). We evaluate these recommendations by reviewing the results of intervention studies that examined the response of red blood cell folate to altered folate intake. Three options are suggested to achieve the extra 400 microg folic acid/d being recommended by the official committees: increased intake of folate-rich foods, dietary folic acid supplementation, and folic acid fortification of food. A significant increase in foods naturally rich in folates was shown to be a relatively ineffective means of increasing red blood cell folate status in women compared with equivalent intakes of folic acid-fortified food, presumably because the synthetic form of the vitamin is more stable and more bioavailable. Although folic acid supplements are highly effective in optimizing folate status, supplementation is not an effective strategy for the primary prevention of NTDs because of poor compliance. Thus, food fortification is seen by many as the only option likely to succeed. Mandatory folic acid fortification of grain products was introduced recently in the United States at a level projected to provide an additional mean intake of 100 microg folic acid/d, but some feel that this policy does not go far enough. A recent clinical trial predicted that the additional intake of folic acid in the United States will reduce NTDs by >20%, whereas 200 microg/d would be highly protective and is the dose also shown to be optimal in lowering plasma homocysteine, with possible benefits in preventing cardiovascular disease. Thus, an amount lower than the current target of an extra 400 microg/d may be sufficient to increase red blood cell folate to concentrations associated with the lowest risk of NTDs, but further investigation is warranted to establish the optimal amount.


Tacrolimus After rATG and Infliximab Induction Immunosuppression-RIMINI Trial.
Infliximab selectively targets recently activated effector cells and, as an induction agent, might enable the safe elimination of mycophenolate from maintenance immunosuppression in kidney transplantation. This is a phase II international multicenter open-label single-arm confidence interval (CI)-based clinical trial of the BIO-DrIM EU consortium aimed at assessing the efficacy and safety of rabbit antithymocyte globulin and infliximab induction in kidney transplantation. Sixty-seven primary kidney transplant recipients at low risk (panel-reactive antibodies <20%, no donor-specific antibodies [DSA]) received rabbit antithymocyte globulin (2 × 1.5 mg/kg, postoperative days 0 and 1) and infliximab (5 mg/kg, postoperative day 2), followed by mycophenolate-free tacrolimus-based immunosuppression for 12 mo. The primary endpoint was efficacy failure, defined as a composite of acute rejection, graft loss, or poor graft function (estimated glomerular filtration rate <40 mL/min) at 12 mo and was based on the endpoint of the comparator study. Additionally, a historical propensity-matched control cohort was established. Primary endpoint occurred in 22 of 67 patients (32.84%), with upper bound of an exact 1-sided 95% CI of 43.47%, which met the predefined criteria (efficacy failure of <40% and upper-bound 95% CI of <50%) and was similar in the historical matched cohort. By 12 mo, 79.1% of patients remained on the study protocol. Lower rates of BK replication (6% versus 22.4%; P = 0.013) but higher rates of de novo DSAs (11.9% versus 1.5%; P = 0.039) were observed in the study cohort. A similar efficacy of the study immunosuppression regimen to the comparator study and the historical matched cohort was found. However, a higher de novo DSA emergence points to an increased risk of antibody-mediated rejection (NCT04114188).


Case studies in outcome-based education.
Outcome-based education is one of the most significant global developments in medical education in recent years. This paper presents four case studies of outcome-based education from medical schools in different parts of the world; Scotland; USA; Pakistan; and Singapore. The outcome-based curricula have either been in place for some time, are evolving or are at the planning proposal stage. The outcomes, change process and implementation of the outcome-based approach are described. Variation in the extent to which each medical school has implemented outcome-based education is discussed and key points for successful implementation are highlighted. This paper is based on the pre-conference symposium "outcome-based curricula: global perspectives" presented by the authors at the 4th Asia Pacific Medical Education Conference (APMEC) in Singapore, 8-11 February, 2007.


Activity of nocturnal primates: influences of twilight zeitgebers and weather.
The time of onset of activity of bush babies (Galago senegalensis), slow lorises (Nycticebus coucang), and an owl monkey (Aotus trivirgatus) living in outdoor enclosures usually fell in certain illuminance ranges of dusk and kept pace with seasonal progressions of sunset time. Influences of cloud cover were variable, but excessive heat and cold were inhibitory. Accurate endogenous timekeeping and reliance on the most stable zeitgeber apparently maintain activities in synchrony with the rhythmically changing environment.


SHP2 is overexpressed and inhibits pSTAT1-mediated APM component expression, T-cell attracting chemokine secretion, and CTL recognition in head and neck cancer cells.
Human leukocyte antigen (HLA) class I antigen processing machinery (APM) component downregulation permits escape of malignant cells from recognition by cytotoxic T lymphocytes (CTL) and correlates with poor prognosis in patients with head and neck cancer (HNC). Activated STAT1 (pSTAT1) is necessary for APM component expression in HNC cells. We investigated whether an overexpressed phosphatase was responsible for basal suppression of pSTAT1 and subsequent APM component-mediated immune escape in HNC cells. Immunohistochemical staining and reverse transcription PCR of paired HNC tumors was performed for the phosphatases src homology domain-containing phosphatase (SHP)-1 and SHP2. Depletion of phosphatase activity in HNC and STAT1(-/-) tumor cells was achieved by siRNA knockdown. HLA class I-restricted, tumor antigen-specific CTL were used in IFN-γ ELISPOT assays against HNC cells. Chemokine secretion was measured after SHP2 depletion in HNC cells. SHP2, but not SHP1, was significantly upregulated in HNC tissues. In HNC cells, SHP2 depletion significantly upregulated expression of pSTAT1 and HLA class I APM components. Overexpression of SHP2 in nonmalignant keratinocytes inhibited IFN-γ-mediated STAT1 phosphorylation, and SHP2 depletion in STAT1(-/-) tumor cells did not significantly induce IFN-γ-mediated APM component expression, verifying STAT1 dependence of SHP2 activity. SHP2 depletion induced recognition of HNC cells by HLA class I-restricted CTL and secretion of inflammatory, T-cell attracting chemokines, RANTES and IP10. These findings suggest for the first time an important role for SHP2 in APM-mediated escape of HNC cells from CTL recognition. Targeting SHP2 could enhance T-cell-based cancer immunotherapy.


Immobilization of enterokinase on magnetic supports for the cleavage of fusion proteins.
Magnetic nanobiocatalysts for tag cleavage on fusion proteins have been prepared by immobilizing enterokinase (EK) onto iron oxide magnetic nanoparticles coated with biopolymers. Two different chemistries have been explored for the covalent coupling of EK, namely carbodiimide (EDC coupling) and maleimide activation (Sulfo coupling). Upon immobilization, EK initial activity lowered but EDC coupling lead to higher activity retention. Regarding the stability of the nanobiocatalysts, these were recycled up to ten times with the greater activity losses observed in the first two cycles. The immobilized EK also proved to cleave a control fusion protein and to greatly simplify the separation of the enzyme from the reaction mixture.


Diel cycling of DNA staining and nifH gene regulation in the unicellular cyanobacterium Crocosphaera watsonii strain WH 8501 (Cyanophyta).
Crocosphaera watsonii WH 8501 is a marine unicellular cyanobacterium that fixes nitrogen primarily during the dark phase of a light-dark (LD) cycle. Circadian clocks modulate gene transcription and cellular activity in many, if not all, cyanobacteria. A model for circadian control has been proposed in cyanobacteria, called the oscilloid model, which is based on topological changes of nucleoid DNA which in turn regulates gene transcription. In this study, the marine unicellular diazotrophic cyanobacteria C. watsonii WH 8501 and Cyanothece sp. ATCC 51142 were found to have daily fluctuations in DNA staining using Hoechst 33342 and SYBR I Green fluorescent dyes. Up to 20-fold decreases in DNA fluorescence of Hoechst-stained cells were observed during the dark phase when cultures were grown with a 12:12 LD cycle or under continuous light (LL). The variation in DNA staining was consistent with changes in DNA topology proposed in the oscilloid model. The abundance of nifH transcripts in C. watsonii WH 8501 was rhythmic under LD and LL cycles, consistent with a circadian rhythm. Cycles of DNA fluorescence and photosynthetic efficiency were disrupted when cultures were shifted into an early dark phase; however, nifH transcripts predictably increased in abundance following the premature transition from light to darkness. Thus, nifH gene expression in C. watsonii WH 8501 appears to be influenced by both circadian and environmental factors.


Prevention, incidence, and outcomes of contrast-induced acute kidney injury.
Little is known about whether health care providers (physicians) implement preventive care for contrast-induced acute kidney injury (CIAKI). The objectives of our prospective cohort study were (1) to assess provider use of preventive strategies for CIAKI, (2) to determine the incidence of CIAKI, and (3) to examine the association of CIAKI with adverse outcomes at 30 days, including death, need for dialysis, and hospital admission. We prospectively identified patients with estimated glomerular filtration rates less than 60 mL/min/1.73 m(2) undergoing procedures with intravascular radiocontrast agents and recorded the use of intravenous fluids and N-acetylcysteine and the discontinuation of nonsteroidal anti-inflammatory medications. We measured postprocedure serum creatinine levels to quantify the incidence of CIAKI and tracked 30-day mortality and need for dialysis or hospitalization to evaluate the association of CIAKI with these outcomes. Preprocedure and postprocedure intravenous fluids were administered to 264 of 660 study patients (40.0%), more commonly with coronary angiography than with computed tomography (91.2% vs 16.6%, P < .001). N-acetylcysteine was administered to 39.2% of patients, while only 6.8% of patients using nonsteroidal anti-inflammatory drugs were instructed to discontinue the medication. In a propensity analysis, the use of intravenous fluids was associated with a reduced rate of CIAKI. The incidence of CIAKI was lowest following computed tomography (range, 0.0%-10.9%) and was highest following noncoronary angiography (range, 1.9%-34.0%). Eleven patients (1.7%) died, 1 patient (0.2%) required dialysis, and 83 patients (12.6%) were hospitalized; however, CIAKI was not independently associated with hospital admission or death. Strategies to prevent CIAKI are implemented nonuniformly. Although biochemical evidence of CIAKI is relatively common, clinically significant CIAKI is rare. These findings should help health care providers focus the use of preventive care on the highest-risk patients and have important implications for future clinical trials.


Enhanced DNA release from disulfide-containing layered nanocomplexes by heparin-electrostatic competition.
Polycationic vectors are often used to deliver DNA for cancer therapies, but their inefficiency in releasing DNA from the polyplexes after endosomal escape limits DNA transcription and their efficient application in vivo. In this study, DNA/PEI polyplexes were cross-linked by a reduction-sensitive disulfide bond and then further complexed with electrostatic competitive heparin (HP) and hyaluronidase (HAase)-sensitive hyaluronate (HA) to obtain DNA/PEIS/HA-HP (DPSHA-HP). DPSHA-HP was stable in an extracellular environment (pH = 7.4) and degraded by HAase after targeted HA receptor CD44-mediated cell endocytosis, causing the outer shielding of the nanocomplex to loosen. The resulting partially exposed disulfide-linked DNA/PEI nanocomplexes efficiently ruptured the endosome, facilitating the cleavage of disulfide bonds and the release of DNA/PEI polyplexes into the cytoplasm, where DNA release from the polyplexes was remarkably enhanced due to strong electrostatic competition of HP with PEI. Consequently, DPSHA-HP exhibited excellent DNA transfection of the target cells, better than disulfide cross-linked DNA/PEI (25 kDa) and DNA/PEIS/HA. Moreover, these novel layered nanocomplexes have high efficiency in down-regulating B-cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1) and exhibit significant inhibition of tumor formation with minimal toxicity in a mouse tumor model.


A giant extrasynovial osteochondroma in the infrapatellar fat pad: end stage Hoffa's disease.
The infrapatellar fat pad of Hoffa is commonly injured but rarely discussed in the orthopaedic literature. Hoffa's disease is the extension of various traumatic events due to impingement and inflammation of the infrapatellar fat pad and known as a vague reason for anterior knee pain. Inflammation is foreground during acute phase of the disease while impingement due to fibrosis and scar tissue of infrapatellar fat pad plays a major role in the chronic phase. The osteochondroma of the infrapatellar fat pad secondary to the Hoffa's disease can be more problematic. Although, the fibrocartilaginous transformation and osteochondral metaplasia of infrapatellar fat pad was pointed out frequently in the literature, the published papers seem far from clarifying the relation between chronic impingement and formation of osteochondroma. We present a case of a giant ossifying chondroma in the infrapatellar fat pad that resulted from chronic Hoffa's disease. Complete open resection was performed successfully after arthroscopic examination. The infrapatellar fat pad contains the entire progenitor cells for the development of an osteochondroma and chronic impingement may have promoter affect on this issue, thus, an osteochondroma may occur at the end-stage Hoffa's disease.


Detection of cervical precancerous lesions with Aptima HPV assays using SurePath preservative fluid specimens.
SurePath specimens from women referred to colposcopy were treated with Aptima Transfer Solution (ATS) before testing in Aptima HPV (AHPV) and Aptima HPV 16, 18/45 (AHPV-GT) assays. Untreated SurePath specimens were tested with the cobas HPV test. PreservCyt specimens were assessed for cytology and tested with AHPV. High-grade cervical intraepithelial neoplasia lesions served as the reference standard. Excellent agreement (95.5%; k=0.91) was observed for ATS-treated SurePath specimens between Tigris and Panther systems and between the PreservCyt and ATS-treated SurePath specimens (91.1%, k=0.81) with the AHPV assay on Tigris. Agreement between the AHPV and cobas assays with SurePath specimens was substantial (89.9%, k=0.80). AHPV sensitivity for CIN2+(n=147) was 91.2% for SurePath and PreservCyt. Cobas HPV sensitivity was 93.9% for SurePath specimens. AHPV testing of SurePath specimens was more specific (59.4%) than cobas (54.7%) (p<0.001). Detection and genotyping showed similar absolute and relative risks. ATS-treated SurePath specimens tested with AHPV and AHPV-GT assays showed similar performance with greater specificity than cobas HPV on SurePath specimens. Similar overall results were seen using a CIN3 disease endpoint.


Reversal of HIV drug resistance and novel strategies to curb HIV infection: the viral infectivity factor Vif as a target and tool of therapy.
Due to the high genetic variability of human immunodeficiency virus (HIV), treatment of AIDS (acquired immunodeficiency syndrome) patients with inhibitors of reverse trancriptase (RT) and drugs blocking the viral protease regularly results in the accumulation of drug resistant HIV variants and treatment failure. The sensitivity of clinically derived resistant HIV-1 strains to nucleotide RT inhibitors could be restored, however, in several laboratories by pharmacological depletion of the appropriate endogenous deoxynucleotide triphosphate (dNTP), and such a manipulation (induction of dCTP pool imbalance during reverse transcription in the presence of a non-nucleoside RT inhibitor) altered the mutation spectrum of the HIV-1 genome, resulting in a lower level of HIV resistance to certain drugs. The cytoplasmic single-stranded DNA cytidine deaminases APOBEC3G and APOBEC3F block HIV replication by introducing premature stop codons into the viral genome. We suggest that the resulting crippled, defective HIV (dHIV) variants could interfere with replication of "wild type" viruses and curbe disese progression in long term non-progressor individuals. Vif, an accessory protein encoded by HIV, counteracts APOBEC3G/F action. We speculate that small molecule inhibitors of Vif could permit lethal or sublethal mutagenesis of HIV genomes. We suggest that an artificial dHIV construct carrying a mutated vif gene (coding for a Vif protein unable to block APOBEC3G/F) could have a therapeutic effect as well in HIV infected individuals and AIDS patients.


Do Patient Delay and Diagnostic Delay Influence Long Term Survival in Patients with Gastric Cancer?
Gastric cancer is one of the most common malignancies, with an aggressive evolution and a poor long-term prognosis. No screening program is available in Europe for this pathology; therefore, the delay from the appearance of the first symptom until the initiation of treatment might influence the prognosis of gastric cancer patients. We aimed to investigate the impact on the prognosis of the delay in the presentation and diagnosis in patients with gastric adenocarcinoma. Our study is a retrospective, single-center, observational cohort study, based on patients diagnosed with gastric adenocarcinoma and operated in our institution between 2013 and 2021. We have defined patient delay as the time from the onset of symptoms to the first encounter with a health care provider and diagnosis delay as the time from the first consultation with a health care provider to the establishment of the final diagnosis. A total of 671 patients were included in our study. The survival rate at 5 years was 55% for the patients operated with curative intent and 7.4% for the patients operated with palliative intent. Patient delay and diagnosis delay were not correlated with the overall survival. A lower survival was observed for patients admitted through transfer (p<0.001) or the emergency department (p<0.001). No statistically significant relationship was identified between patient delay or diagnosis delay and the age, gender or area of origin of patients. Patients that experienced melena or hematemesis had a shorter patient delay, with a highly significant statistical relationship (p<0.01). Patients that experienced nausea, epigastric pain, palpable epigastric tumor mass or anorexia also had a highly significant statistical relationship between the symptoms and the patient delay interval. The overall survival is not influenced by the patient delay or diagnosis delay. An earlier presentation was correlated with some specific exhibited symptoms: upper gastro-intestinal bleeding, abdominal pain, palpable epigastric tumor, nausea.


Neural correlates of binding lyrics and melodies for the encoding of new songs.
Songs naturally bind lyrics and melody into a unified representation. Using a subsequent memory paradigm, we examined the neural processes associated with binding lyrics and melodies during song encoding. Participants were presented with songs in two conditions: a unified condition (melodies sung with lyrics), and a separate condition (melodies sung with the syllable "la"). In both cases, written lyrics were displayed and participants were instructed to memorize them by repeating them covertly or by generating mental images of the songs. We expected the unified condition to recruit the posterior superior temporal gyrus, known to be involved in perceptual integration of songs, as well as the left inferior frontal gyrus (IFG). Conversely, we hypothesized that the separate condition would engage a larger network including the hippocampus to bind lyrics and melodies of songs, and the basal ganglia and the cerebellum to ensure the correct sequence coupling of verbal and musical information in time. Binding lyrics and melodies in the unified condition revealed activation of the left IFG, bilateral middle temporal gyrus (MTG), and left motor cortex, suggesting a strong linguistic processing for this condition. Binding in the separate compared to the unified condition revealed greater activity in the right hippocampus as well as other areas including the left caudate, left cerebellum, and right IFG. This study provides novel evidence for the role of the right hippocampus in binding lyrics and melodies in songs. Results are discussed in light of studies of binding in the visual domain and highlight the role of regions involved in timing and synchronization such as the basal ganglia and the cerebellum.


Utility of NT-proBNP for identifying LV failure in patients with acute exacerbation of chronic bronchitis.
NT-proBNP has been widely regarded as a useful tool for diagnosis or exclusion of heart failure (HF) in many settings. However, in patients with acute exacerbation of chronic bronchitis (AECB), its roles have not been well described. The objective of this study was to evaluate the diagnostic performance of NT-proBNP for identifying left ventricular (LV) failure in such patients. 311 AECB patients and 102 stable chronic bronchitis patients with no history of HF were enrolled. Plasma NT-proBNP concentrations were measured using Roche Elecsys. The European Society of Cardiology (ESC) diagnostic principles were adopted to identify HF and the diagnostic performance of NT-proBNP was evaluated by ROC. Our results showed, the median NT-proBNP level in patients with LV failure [4828.4 (2044.4-9203.6) ng/L] was significantly higher than that in those without LV failure [519.2 (179.1-1409.8) ng/L, p<0.001] and stable controls [207.5 (186.5-318.2) ng/L, p<0.001]. LV failure, renal function, atrial fibrillation and systolic pulmonary artery pressure were independent predictors of NT-proBNP levels (all p<0.05). The area under ROC curve (AUC) of NT-proBNP for identifying LV failure was 0.884, significantly superior to clinical judgment alone (AUC 0.835, p = 0.0294). At the optimal cutoff value of 935.0 ng/L, NT-proBNP yielded sensitivity 94.4%, specificity 68.2%, accuracy 74.3% and negative predictive value 97.6%. Adding the results of NT-proBNP to those of clinical judgment improved the diagnostic accuracy for LV failure. As a tool for diagnosis or exclusion of HF, NT-proBNP can help physicians identify LV failure in patients with AECB.


Validation of the United Kingdom copy-number alteration classifier in 3239 children with B-cell precursor ALL.
Genetic abnormalities provide vital diagnostic and prognostic information in pediatric acute lymphoblastic leukemia (ALL) and are increasingly used to assign patients to risk groups. We recently proposed a novel classifier based on the copy-number alteration (CNA) profile of the 8 most commonly deleted genes in B-cell precursor ALL. This classifier defined 3 CNA subgroups in consecutive UK trials and was able to discriminate patients with intermediate-risk cytogenetics. In this study, we sought to validate the United Kingdom ALL (UKALL)-CNA classifier and reevaluate the interaction with cytogenetic risk groups using individual patient data from 3239 cases collected from 12 groups within the International BFM Study Group. The classifier was validated and defined 3 risk groups with distinct event-free survival (EFS) rates: good (88%), intermediate (76%), and poor (68%) (P < .001). There was no evidence of heterogeneity, even within trials that used minimal residual disease to guide therapy. By integrating CNA and cytogenetic data, we replicated our original key observation that patients with intermediate-risk cytogenetics can be stratified into 2 prognostic subgroups. Group A had an EFS rate of 86% (similar to patients with good-risk cytogenetics), while group B patients had a significantly inferior rate (73%, P < .001). Finally, we revised the overall genetic classification by defining 4 risk groups with distinct EFS rates: very good (91%), good (81%), intermediate (73%), and poor (54%), P < .001. In conclusion, the UKALL-CNA classifier is a robust prognostic tool that can be deployed in different trial settings and used to refine established cytogenetic risk groups.


Doubling up on function: dual-specificity tyrosine-regulated kinase 1A (DYRK1A) in B cell acute lymphoblastic leukemia.
DYRK1A, the dual-specificity kinase, is again doubling up on function, as reported by Bhansali, Rammohan, and colleagues in this issue of the JCI. DYRK1A is an evolutionarily conserved protein kinase with dual specificity; it adds phosphates to serine/threonine residues of diverse regulatory proteins and activates its own function by autophosphorylating a critical tyrosine at position 321 in the activation loop. Bhansali, Rammohan, and colleagues investigated B cell acute lymphoblastic leukemia (B-ALL) in individuals with Down syndrome (DS) and in children with leukemia characterized by aneuploidy. The study revealed a DYRK1A/FOXO1 and STAT3 signaling pathway in B-ALL that could be targeted pharmacologically, thus opening the door to therapeutic strategies for patients with leukemia with or without DS.


Delivery of Peptidic Gonadotropin Releasing Hormone Antagonists.
GnRH antagonists have several clinical applications in prostate cancer, regulation of ovulation induction in females, breast cancer, male contraception and others. Antagonists differ from natural GnRH decapeptide in having five or more amino acid substitutions, whereas most of the antagonists are available as subcutaneous (SC) formula for injection some are formulated as a depot formulation for sustained release (e.g., Cetrorelix, Degarelix). Systemic delivery of cetrorelix acetate by intratracheal route can be achieved using dry powder for inhalation of the adhesive mixture when the powder deposition reaches stage four. The oral route for systemic delivery of peptide without its degradation can be achieved using gastrointestinal permeation enhancement technology GIPET® provided by acyline.


[Excitation and inhibition of highly excitable reflex curves in chronically denervated albino rats].
The animals were selected with spastic syndrome and enlarged amplitude of monosynaptic segmental reflex responses in 2-4 weeks after cutting of spinal cord at Th10 level. The processes of excitation and inhibition in lumbar segments of these animals were investigated. A reliable decrease of the presynaptic inhibition intensity was found after cutting of spinal cord. It is supposed that reduction of presynaptic inhibition plays a definite but not determinant role in developing hyperreflexia in chronically spinal white rat.


Environmental conditions and plant physiology modulate Cu phytotoxicity in field-contaminated soils.
Foliar Cu concentration has been widely used as a biomarker of plant growth in phytotoxicity bioassays. This relation has helped find plant processes altered by Cu in dose-response experiments (a bivariate approach). However, when plants are grown in field conditions, their responses can vary in function of multiple variables, such as the environment, plant physiology, and other elements in plant (plant ionome). These sources of variability are commonly unreported, which could limit bioassays' utility. Thus, the present study aimed to assess and integrate the mentioned sources of variability on Cu phytotoxicity. Lettuce was used as plant model. Lettuces were grown in growth chambers with contrasting light and air humidity conditions and on two different field-contaminated soils (sandy and loamy soils). Results showed that environmental conditions significantly affected foliar Cu and plant growth, but this effect differed in the two studied soils. Foliar Cu was not a good biomarker of plant growth. In contrast, integrating the potential phytotoxicity effect with the plant's nutritional status allowed a better understanding of plant growth. We remarked on using a structural equation modeling approach (SEM) to integrate plant physiology and plant ionome as moderators of plant growth. Results showed that plant growth was primarily related to plant nutritional status rather than Cu phytotoxicity. Also, the foliar Cu concentration would affect plant nutritional status due to photosynthesis-related plant processes and cation balance. Finally, this research invites to state and include sources of variability when assessing phytotoxicity. This way, it is possible to advance toward understanding complex linked processes occurring in field conditions.


Microwave image reconstruction from 3-D fields coupled to 2-D parameter estimation.
An efficient Gauss-Newton iterative imaging technique utilizing a three-dimensional (3-D) field solution coupled to a two-dimensional (2-D) parameter estimation scheme (3-D/2-D) is presented for microwave tomographic imaging in medical applications. While electromagnetic wave propagation is described fully by a 3-D vector field, a 3-D scalar model has been applied to improve the efficiency of the iterative reconstruction process with apparently limited reduction in accuracy. In addition, the image recovery has been restricted to 2-D but is generalizable to three dimensions. Image artifacts related primarily to 3-D effects are reduced when compared with results from an entirely two-dimensional inversion (2-D/2-D). Important advances in terms of improving algorithmic efficiency include use of a block solver for computing the field solutions and application of the dual mesh scheme and adjoint approach for Jacobian construction. Methods which enhance the image quality such as the log-magnitude/unwrapped phase minimization were also applied. Results obtained from synthetic measurement data show that the new 3-D/2-D algorithm consistently outperforms its 2-D/2-D counterpart in terms of reducing the effective imaging slice thickness in both permittivity and conductivity images over a range of inclusion sizes and background medium contrasts.


Executive control and learning pattern on the CVLT.
We evaluated a 23 year-old man after recovery from encephalitis. In contrast to the expected pattern of increasingly better acquisition across the 5 learning trials of the California Verbal Learning Test (CVLT-2), he produced a "J-shaped" curve (Trials 1-5: 8,6,6,9,11). Because he also demonstrated excessive levels of proactive interference as well as poor divided attention, we hypothesized that his atypical learning pattern was due to a build-up of proactive interference secondary to executive dyscontrol. Using a large sample of 4462 healthy adult men, we identified four groups exhibiting various learning patterns. We found that a learning pattern similar to this patient (i.e., a drop after trial 1 followed by recovery) was rare (1.1% of the sample). Individuals with this learning pattern demonstrated increased perseverative responses, as well as greater difficulty maintaining cognitive set on the Wisconsin Card Sorting Test, decreased attentional control on the Paced Auditory Serial Addition Test, and greater levels of proactive interference on the CVLT. Taken together, the results of the study suggest that an early drop, followed by a recovery in learning trial performance, is associated with executive dyscontrol.


Understanding what we know so far about young people's engagement with wellbeing apps. A scoping review and narrative synthesis.
Increased levels of wellbeing contribute to people being more productive, resilient, physically healthy and showing lower levels of mental illness. Using mobile apps to increase wellbeing in young people is becoming the method of choice. This study sought to critically appraise the current evidence base with regards to young people's (16-24 years of age) engagement with wellbeing apps. A systematic review of the literature and narrative synthesis was conducted to investigate users' characteristics and other potential engagement elements. A total of 11,245 titles, 160 abstracts and 68 full-text articles published between 2002 and 2021 were screened, of which 22 studies were included. Main themes/findings indicated that a user's engagement with wellbeing apps was dependant on the presence of strong identity elements, including motivation, mood and values; design elements such as meaningful rewards, short duration of studies and seamless automatic delivery with low contact with researchers; and being innovative and contextualised. The majority of the studies did not report outcomes by social determinants such as ethnicity, education and others. This research reflects on the need to consider participants' individuality when designing app mediated wellbeing interventions.


Evaluation of discontinuation for adverse events of JAK inhibitors and bDMARDs in an international collaboration of rheumatoid arthritis registers (the 'JAK-pot' study).
In a clinical trial setting, patients with rheumatoid arthritis (RA) taking the Janus kinase inhibitor (JAKi) tofacitinib demonstrated higher adverse events rates compared with those taking the tumour necrosis factor inhibitors (TNFi) adalimumab or etanercept. Compare treatment discontinuations for adverse events (AEs) among second-line therapies in an international real-world RA population. Patients initiating JAKi, TNFi or a biological with another mode of action (OMA) from 17 registers participating in the 'JAK-pot' collaboration were included. The primary outcome was the rate of treatment discontinuation due to AEs. We used unadjusted and adjusted cause-specific Cox proportional hazard models to compare treatment discontinuations for AEs among treatment groups by class, but also evaluating separately the specific type of JAKi. Of the 46 913 treatment courses included, 12 523 were JAKi (43% baricitinib, 40% tofacitinib, 15% upadacitinib, 2% filgotinib), 23 391 TNFi and 10 999 OMA. The adjusted cause-specific hazard rate of treatment discontinuation for AEs was similar for TNFi versus JAKi (1.00, 95% CI 0.92 to 1.10) and higher for OMA versus JAKi (1.11, 95% CI 1.01 to 1.23), lower with TNFi compared with tofacitinib (0.81, 95% CI 0.71 to 0.90), but higher for TNFi versus baricitinib (1.15, 95% CI 1.01 to 1.30) and lower for TNFi versus JAKi in patients 65 or older with at least one cardiovascular risk factor (0.79, 95% CI 0.65 to 0.97). While JAKi overall were not associated with more treatment discontinuations for AEs, subgroup analyses suggest varying patterns with specific JAKi, such as tofacitinib, compared with TNFi. However, these observations should be interpreted cautiously, given the observational study design.


Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth.
Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. Treatment of HCC is complicated by the fact that the disease is often diagnosed at an advanced stage when it is no longer amenable to curative surgery, and current systemic chemotherapeutics are mostly inefficacious. Sirtuin 1 (SIRT1) is a class III histone deacetylase that is implicated in gene regulations and stress resistance. In this study, we found that SIRT1 is essential for the tumorigenesis of HCC. We showed that although SIRT1 was expressed at very low levels in normal livers, it was overexpressed in HCC cell lines and in a subset of HCC. Tissue microarray analysis of HCC and adjacent nontumoral liver tissues revealed a positive correlation between the expression levels of SIRT1 and advancement in tumor grades. Downregulation of SIRT1 consistently suppressed the proliferation of HCC cells via the induction of cellular senescence or apoptosis. SIRT1 silencing also caused telomere dysfunction-induced foci and nuclear abnormality that were clearly associated with reduced expressions of telomerase reverse transcriptase (TERT), and PTOP, which is a member of the shelter in complex. Ectopic expression of either TERT or PTOP in SIRT1-depleted cells significantly restored cell proliferation. There was also a positive correlation between the level of induction of SIRT1 and TERT [corrected] in human HCC. Finally, SIRT1-silencing sensitized HCC cells to doxorubicin treatment. Together, our findings reveal a novel function for SIRT1 in telomere maintenance of HCC, and they rationalize the clinical exploration of SIRT1 inhibitors for HCC therapy.


Treatment of the cavus foot. Deformity in the pediatric patient with Charcot-Marie-Tooth.
The orthopedic management of foot and ankle problems associated with Charcot-Marie-Tooth disease is becoming better understood but is still evolving. It is now known that Charcot-Marie-Tooth disease should be considered a spectrum of neurologic disorders with variable inheritance patterns, clinical course, and severity of deformities. Over half of the patients with Charcot-Marie-Tooth disease develop foot and ankle problems of which the cavovarus deformity is by far the commonest. Other clinical problems include weakness, parathesias, pain, and an unsteady gait. The cavovarus deformity seems to develop from a relative imbalance between the peroneus longus and tibialis anterior muscles and from an imbalance between the tibialis posterior and peroneus brevis muscles. Treatment of the cavovarus foot deformities should be individualized for each patient after careful preoperative evaluation. Surgery using a variety of soft tissue procedures and osteotomies seems to be the treatment of choice for the progressive cavovarus deformity in younger patients. For a patient who has severely rigid deformities a triple arthrodesis may be the only option but is considered by most to be a salvage procedure. It always should be kept in mind that Charcot-Marie-Tooth disease is a progressive neurologic disorder and the deformities can progress despite surgical intervention. Even though the results of treatment in this disease are difficult to evaluate because of the wide [figure: see text] spectrum of disease, it seems reasonable to believe that early surgical intervention in the flexible cavus foot can restore normal foot posture and help prevent or delay the need for more extensive bony procedures.


The European multicenter trial on the safety and efficacy of guided oblique lumbar interbody fusion (GO-LIF).
Because of the implant-related problems with pedicle screw-based spinal instrumentations, other types of fixation have been tried in spinal arthrodesis. One such technique is the direct trans-pedicular, trans-discal screw fixation, pioneered by Grob for spondylolisthesis. The newly developed GO-LIF procedure expands the scope of the Grob technique in several important ways and adds security by means of robotic-assisted navigation. This is the first clinical trial on the GO-LIF procedure and it will assess safety and efficacy. Multicentric prospective study with n = 40 patients to undergo single level instrumented spinal arthrodesis of the lumbar or the lumbosacral spine, based on a diagnosis of: painful disc degeneration, painful erosive osteochondrosis, segmental instability, recurrent disc herniation, spinal canal stenosis or foraminal stenosis. The primary target criteria with regards to safety are: The number, severity and cause of intra- and perioperative complications. The number of significant penetrations of the cortical layer of the vertebral body by the implant as recognized on postoperative CT. The primary target parameters with regards to feasibility are: Performance of the procedure according to the preoperative plan. The planned follow-up is 12 months and the following scores will be evaluated as secondary target parameters with regards to clinical improvement: VAS back pain, VAS leg pain, Oswestry Disability Index, short form - 12 health questionnaire and the Swiss spinal stenosis questionnaire for patients with spinal claudication. The secondary parameters with regards to construct stability are visible fusion or lack thereof and signs of implant loosening, implant migration or pseudarthrosis on plain and functional radiographs. This trial will for the first time assess the safety and efficacy of guided oblique lumbar interbody fusion. There is no control group, but the results, the outcome and the rate of any complications will be analyzed on the background of the literature on instrumented spinal fusion. Despite its limitations, we expect that this study will serve as the key step in deciding whether a direct comparative trial with another fusion technique is warranted. Clinical Trials NCT00810433.


Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress.
A series of synthetic triterpenoid (TP) analogues of oleanolic acid are powerful inhibitors of cellular inflammatory processes such as the induction by IFN-gamma of inducible nitric oxide synthase (iNOS) and of cyclooxygenase 2 in mouse macrophages. Here, we show that these analogues are also extremely potent inducers of the phase 2 response [e.g., elevation of NAD(P)H-quinone oxidoreductase and heme oxygenase 1], which is a major protector of cells against oxidative and electrophile stress. Moreover, like previously identified phase 2 inducers, the TP analogues use the antioxidant response element-Nrf2-Keap1 signaling pathway. Thus, induction of the phase 2 response and suppression of the iNOS induction was abrogated in nrf2(-/-) and keap1(-/-) mouse embryonic fibroblasts. The high potency of TP analogues in inducing the phase 2 response and blocking inflammation depends on the presence of activated Michael reaction (enone) functions at critical positions in rings A and C. The most potent TP doubles NAD(P)H-quinone oxidoreductase in murine hepatoma cells at 0.28 nM and has an IC(50) for suppression of iNOS induction in primary mouse macrophages of 0.0035 nM. The direct interaction of this TP with thiol groups of the Keap1 sensor for inducers is demonstrated spectroscopically. The antiinflammatory and phase 2 inducer potencies of 18 TP are closely linearly correlated (r(2) = 0.91) over 6 orders of magnitude of concentration. Thus, in addition to blocking inflammation and promoting differentiation, these TP exhibit another very important protective property: the induction of the phase 2 response.


Predictive validity and classification accuracy of ActiGraph energy expenditure equations and cut-points in young children.
Evaluate the predictive validity of ActiGraph energy expenditure equations and the classification accuracy of physical activity intensity cut-points in preschoolers. Forty children aged 4-6 years (5.3±1.0 years) completed a ∼150-min room calorimeter protocol involving age-appropriate sedentary, light and moderate-to vigorous-intensity physical activities. Children wore an ActiGraph GT3X on the right mid-axillary line of the hip. Energy expenditure measured by room calorimetry and physical activity intensity classified using direct observation were the criterion methods. Energy expenditure was predicted using Pate and Puyau equations. Physical activity intensity was classified using Evenson, Sirard, Van Cauwenberghe, Pate, Puyau, and Reilly, ActiGraph cut-points. The Pate equation significantly overestimated VO2 during sedentary behaviors, light physical activities and total VO2 (P<0.001). No difference was found between measured and predicted VO2 during moderate-to vigorous-intensity physical activities (P = 0.072). The Puyau equation significantly underestimated activity energy expenditure during moderate-to vigorous-intensity physical activities, light-intensity physical activities and total activity energy expenditure (P<0.0125). However, no overestimation of activity energy expenditure during sedentary behavior was found. The Evenson cut-point demonstrated significantly higher accuracy for classifying sedentary behaviors and light-intensity physical activities than others. Classification accuracy for moderate-to vigorous-intensity physical activities was significantly higher for Pate than others. Available ActiGraph equations do not provide accurate estimates of energy expenditure across physical activity intensities in preschoolers. Cut-points of ≤25 counts⋅15 s(-1) and ≥420 counts⋅15 s(-1) for classifying sedentary behaviors and moderate-to vigorous-intensity physical activities, respectively, are recommended.


Rel/NF-kappaB represses bcl-2 transcription in pro-B lymphocytes.
The mechanisms controlling programmed cell death (PCD) during early B cell development are not well understood. Members of both the Bcl-2 family of apoptosis-related proteins and the nuclear factor-kappa B/Rel (NF-kappaB/Rel) family of transcription factors are expressed differentially during B cell development. To date, however, no direct interactions between these two families have been demonstrated. The FL5.12 cell line represents a model for progenitor B cell development. Such cells reproducibly undergo PCD upon IL-3 withdrawal. The signal to enter the apoptotic pathway is mediated by a shift in the ratio of Bcl-2:Bax. While bax levels remain constant, bcl-2 transcription rate, steady-state mRNA, and protein levels decrease. Analysis of the bcl-2 promoter reveals 3 kappaB sites functionally able to bind kappaB factors from FL5.12 nuclear extracts. Cotransfection studies demonstrate that NF-kappaB factors can repress bcl-2 transcription and that site-directed mutagenesis of the kappaB motifs abolishes this repression. These studies suggest that NF-kappaB mediates PCD in pro-B cells through transcriptional repression of the survival gene bcl-2, thus shifting the bcl-2:bax ratio in favor of death-promoting complexes.


Clinicopathological characteristics of lymphoproliferative disorders in 232 patients with rheumatoid arthritis in Japan: A retrospective, multicenter, descriptive study.
To describe the clinicopathological characteristics of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA). In this multicenter case series, we retrospectively reviewed the medical records of RA patients who were newly diagnosed as having LPDs with or without biopsy confirmation between 2000 and 2017 in eight hospitals in Japan. We included 232 patients with LPDs. The median age was 67 years (interquartile range [IQR], 60-73 years), and 77.1% were female. At the time of LPD diagnosis, 94.8% and 62.6% of the patients were methotrexate users and in remission or had low RA disease activity, respectively; lymphadenopathy and extranodal involvement were present in 77.1% and 51.9%, respectively. Major extranodal sites were the lungs and oral/oropharyngeal mucosa. The most common LPD pathological subtype was diffuse large B-cell lymphoma (40.5%), followed by classic Hodgkin lymphoma (10.8%), Epstein-Barr virus-positive mucocutaneous ulcer (7.7%), and reactive lymphoid hyperplasia (6.2%). The clinical and laboratory characteristics varied across the pathological subtypes. LPD occurred mainly in methotrexate users, while RA disease activity did not seem to be associated with LPD development. Although the clinical manifestations vary among pathological subtypes, manifestations of LPD in patients with RA can include lymphadenopathy, extranodal mass, and mucocutaneous ulcer.


Targeting the E2F1/Rb/HDAC1 axis with the small molecule HR488B effectively inhibits colorectal cancer growth.
Colorectal cancer (CRC), the third most common cancer worldwide, remains highly lethal as the disease only becomes symptomatic at an advanced stage. Growing evidence suggests that histone deacetylases (HDACs), a group of epigenetic enzymes overexpressed in precancerous lesions of CRC, may represent promising molecular targets for CRC treatment. Histone deacetylase inhibitors (HDACis) have gradually become powerful anti-cancer agents targeting epigenetic modulation and have been widely used in the clinical treatment of hematologic malignancies, while only few studies on the benefit of HDACis in the treatment of CRC. In the present study, we designed a series of small-molecule Thiazole-based HDACis, among which HR488B bound to HDAC1 with a high affinity and exerted effective anti-CRC activity both in vitro and in vivo. Moreover, we revealed that HR488B specifically suppressed the growth of CRC cells by inducing cell cycle G0/G1 arrest and apoptosis via causing mitochondrial dysfunction, reactive oxygen species (ROS) generation, and DNA damage accumulation. Importantly, we noticed that HR488B significantly decreased the expression of the E2F transcription factor 1 (E2F1), which was crucial for the inhibitory effect of HR488B on CRC. Mechanistically, HR488B obviously decreased the phosphorylation level of the retinoblastoma protein (Rb), and subsequently prevented the release of E2F1 from the E2F1/Rb/HDAC1 complex, which ultimately suppressed the growth of CRC cells. Overall, our study suggests that HR488B, a novel and efficient HDAC1 inhibitor, may be a potential candidate for CRC therapy in the future. Furthermore, targeting the E2F1/Rb/HDAC1 axis with HR488B provides a promising therapeutic avenue for CRC.


[Patients' experience with treatment of chronic fatigue syndrome].
Chronic fatigue syndrome is a highly debated condition. Little is known about causes and treatment. Patients" experience is important in this context. 828 persons with chronic fatigue syndrome (ICD-10 code: G93.3) were included in the study. They were recruited through two Norwegian patient organizations (ME-association and MENiN). The participants filled in a questionnaire on their experience with various approaches to alleviate their condition. Pacing was evaluated as useful by 96% of the participants, rest by 97%, and 96% of the participants considered complete shielding and quietness to be useful. 57% of the participants who had received help to identify and challenge negative thought patterns regarded this useful. 79% of the participants with experience from graded training regarded this to worsen their health status. Overall, the results were similar, irrelevant of the severity of the condition. Most participants in this study evaluated pacing, rest and complete shielding and quietness to be useful. The experience of the participants indicate that cognitive behaviour therapy can be useful for some patients, but that graded training may cause deterioration of the condition in many patients. The results must, however, be interpreted with care, as the participants are not a representative sample, and we do not know the specific content of the approaches.


The interaction of morphine and gamma-aminobutyric acid (GABA)ergic systems in anxiolytic behavior: using mu-opioid receptor knockout mice.
We investigated the interaction of morphine and gamma-aminobutyric acid (GABA)ergic systems in anxiolytic action using mu-opioid receptor knockout and wild-type female mice. An elevated plus-maze test was used to assess anxiolytic behavior. The anxiolytic activities were monitored after experimental animals were pretreated with morphine [15 mg/kg, subcutaneous (s.c.)] and 3 h later received a single dose of muscimol (0.5 mg/kg, s.c.). In another experiment, mice received a single dose of opioid antagonist, naloxone [1.0 mg/kg, intraperitoneal (i.p.)], or GABA(A) receptor antagonist, (+)bicucullin (2.0 mg/kg, i.p.), 2.5 h after the morphine and 30 min before the muscimol injection. Control mice received vehicle only. The results show that morphine enhanced muscimol-induced staying time in open arms by 160% in wild-type mice. Moreover, the effect of morphine in the wild type was inhibited by the pretreatment of either naloxone or (+)bicucullin. Autoradiographic analysis indicated that morphine-administration raised [(3)H]muscimol binding by around 25% of the basal level in posterior thalamic, mediodorsal thalamic, and amygdaloid areas, but not in the hippocampal area in wild-type mice. In contrast, morphine administration did not alter the [(3)H]muscimol binding in mu-opioid receptor knockout mice. The present results reveal that mu-opioid receptor may play a role in the modification of anxiolytic behavior regulated by GABAergic neurotransmission.


The power dynamics perpetuating unsafe abortion in Africa: a feminist perspective.
Tens of thousands of African women die every year because societies and governments either ignore the issue of unsafe abortion or actively refuse to address it. This paper explores the issue of abortion from a feminist perspective, centrally arguing that finding appropriate strategies to reclaim women's power at an individual and social level is a central lever for developing effective strategies to increase women's access to safe abortion services. The paper emphasises the central role of patriarchy in shaping the ways power plays itself out in individual relationships, and at social, economic and political levels. The ideology of male superiority denies abortion as an important issue of status and frames the morality, legality and socio-cultural attitudes towards abortion. Patriarchy sculpts unequal gender power relationships and takes power away from women in making decisions about their bodies. Other forms of power such as economic inequality, discourse and power within relationships are also explored. Recommended solutions to shifting the power dynamics around the issue include a combination of public health, rights-based, legal reform and social justice approaches.


Lipoteichoic acid-binding and biological properties of T protein of group A streptococcus.
T protein was extracted with trypsin from an avirulent, M protein-deficient, type 1 group A Streptococcus and purified by ammonium sulfate precipitation and anion-exchange chromatography. The latter procedure removed contaminating lipoteichoic acid (LTA) from the T protein, which consisted of a heterogeneous mixture of polypeptides resistant to digestion by trypsin and ranged in molecular size from 160,000 to 200,000 daltons. Threonine, aspartic acid, glutamic acid, lysine, and valine were the most predominant amino acids. The binding of LTA to an affinity column of T protein was reversible with increasing concentrations of ethanol but not with increasing ionic strength. T protein bound less palmitic acid and LTA than did fatty acid-free bovine albumin and did not stimulate human peripheral lymphocytes. Because the surface and cell wall distribution of the T proteins and LTA appear similar, the possibility exists that T proteins and LTA may interact in situ by weakly hydrophobic bonds. Such ligand-ligand interaction may be indirectly involved in the adherence of group A streptococci to host cell membranes that is known to be mediated by LTA.


Patient controlled analgesia in pediatrics.
Patient controlled analgesia is a new, upcoming method of managing pain in the pediatric population. Introducing it to the nursing division of a children's hospital requires that the nursing staff development educator assess, plan, implement, and evaluate its method of introduction and use. The educator must involve multidisciplinary team members to facilitate this change.


Information transfer in multienzyme complexes--2. The role of Arg64 of Chlamydomonas reinhardtii phosphoribulokinase in the information transfer between glyceraldehyde-3-phosphate dehydrogenase and phosphoribulokinase.
A mutant phosphoribulokinase has been isolated from the 12-2B mutant of Chlamydomonas reinhardtii. In this mutant, Arg64 has been replaced by Cys. The enzyme, which may exist in the dimeric and tetrameric states, is almost devoid of activity. Neither of these enzymes is able to form a complex with glyceraldehyde-3-phosphate dehydrogenase. The phosphoribulokinase gene has been expressed in Escherichia coli. The resulting recombinant protein, after isolation and purification, is apparently identical to the native enzyme extracted from the chloroplast. Three mutants have been generated by site directed mutagenesis. Arg64 has been replaced by Ala, Lys or Glu. With the exception of the latter, the two other mutants, [A64]phosphoribulokinase and [K64]phosphoribulokinase, are active when they are reduced, and nearly totally inactive in their oxidized state. Their activity, however, is decreased relative to that of the native, or to that of the wild-type recombinant phosphoribulokinase. Both the catalytic constant and the apparent affinity of ribulose 5-phosphate are decreased relative to the corresponding values obtained for the wild-type, the native or the recombinant enzyme. Whereas the [A64]phosphoribulokinase is unable to form a complex with glyceraldehyde-3-phosphate dehydrogenase, [K64]phosphoribulokinase does, but the stability of the resulting complex is much decreased relative to that of the wild-type complex. The oxidized mutant [K64]phosphoribulokinase becomes active in the presence of glyceraldehyde-3-phosphate dehydrogenase but this activity is smaller than that of the corresponding wild-type enzyme. Taken together, these results show that Arg64 plays a major role in the association of the two enzymes and in the information transfer that takes place between glyceraldehyde-3-phosphate dehydrogenase and phosphoribulokinase. As this residue also appears to be important for catalytic activity, it may be tempting to consider that it stabilizes a conformation that is required for both the catalytic activity and the formation of the bienzyme complex.


Vascular anomaly cases for the pediatric hematologist oncologists-An interdisciplinary review.
Vascular anomalies (VAs) are classified as tumors or malformations depending on their clinical characteristics, pathological diagnosis, and genomic information. Diagnosis can be challenging because of the heterogeneity of clinical presentation; thus, the best diagnosis and care are provided by an interdisciplinary team of specialists. Over the past 10 years, an increasing number of pediatric hematologist/oncologists are caring for patients with VAs secondary to new medical therapy options and clinical trials. This paper focuses on complicated VA issues often seen by the pediatric hematologist/oncologist. The paper reviews clinical pearls on diagnosis, histology, radiology, and treatment options.


Polymorphisms in the gene encoding bovine interleukin-10 receptor alpha are associated with Mycobacterium avium ssp. paratuberculosis infection status.
Johne's disease is a chronic inflammatory bowel disease (IBD) of ruminants caused by Mycobacterium avium ssp. paratuberculosis (MAP). Since this pathogen has been implicated in the pathogenesis of human IBDs, the goal of this study was to assess whether single nucleotide polymorphism (SNPs) in several well-known candidate genes for human IBD are associated with susceptibility to MAP infection in dairy cattle. The bovine candidate genes, interleukin-10 (IL10), IL10 receptor alpha/beta (IL10RA/B), transforming growth factor beta 1 (TGFB1), TGFB receptor class I/II (TGFBR1/2), and natural resistance-associated macrophage protein 1 (SLC11A1) were sequenced for SNP discovery using pooled DNA samples, and the identified SNPs were genotyped in a case-control association study comprised of 242 MAP negative and 204 MAP positive Holstein dairy cattle. Logistic regression was used to determine the association of SNPs and reconstructed haplotypes with MAP infection status. A total of 13 SNPs were identified. Four SNPs in IL10RA (984G > A, 1098C > T, 1269T > C, and 1302A > G) were tightly linked, and showed a strong additive and dominance relationship with MAP infection status. Haplotypes AGC and AAT, containing the SNPs IL10RA 633C > A, 984G > A and 1185C > T, were associated with an elevated and reduced likelihood of positive diagnosis by serum ELISA, respectively. SNPs in IL10RA are associated with MAP infection status in dairy cattle. The functional significance of these SNPs warrants further investigation.


Involvement of Up-regulation of Death Receptors and Bim in Hispolon-mediated TNF-related Apoptosis-inducing Ligand Sensitization in Human Renal Carcinoma.
Hispolon has been shown to possess antitumor effects in various cancer cells. However, the underlying mechanisms are not fully understood. In this study, we evaluated the sensitizing effect of hispolon on TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human renal carcinoma cells. Apoptosis was analyzed by using cell-based cytometer. The mRNA levels were assessed by reverse transcription-PCR. Bax activation was determined by oligomerization and fluorescence-activated cell sorting with Bax-NT monoclonal antibody. The protein expression was measured by Western blotting. Hispolon induced up-regulation of Bim and death receptors expression at the post-translational level. Hispolon enhanced TRAIL-mediated apoptosis in renal carcinoma cells, but not in normal cells.


High-pressure polymorphism of BaFe2Se3.
BaFe2Se3 is a potential superconductor material exhibiting transition at 11 K and ambient pressure. Here we extended the structural and performed electrical resistivity measurements on this compound up to 51 GPa and 20 GPa, respectively, in order to distinguish if the superconductivity in this sample is intrinsic to the BaFe2Se3 phase or if it is originating from minor FeSe impurities that show a similar superconductive transition temperature. The electrical resistance measurements as a function of pressure show that at 5 GPa the superconducting transition is observed at around 10 K, similar to the one previously observed for this sample at ambient pressure. This indicates that the superconductivity in this sample is most likely intrinsic to the BaFe2Se3 phase and not to FeSe with T c > 20 K at these pressures. Further increase in pressure suppressed the superconductive signal and the sample remained in an insulating state up to the maximum achieved pressure of 20 GPa. Single-crystal and powder x-ray diffraction measurements revealed two structural transformations in BaFe2Se3: a second order transition above 3.5 GPa from Pnma (CsAg2I3-type structure) to Cmcm (CsCu2Cl3-type structure) and a first order transformation at 16.6 GPa. Here, γ-BaFe2Se3 transforms into δ-BaFe2Se3 (Cmcm, CsCu2Cl3-type average structure) via a first order phase transition mechanism. This transition is characterized by a significant shortening of the b lattice parameter of γ-BaFe2Se3 (17%) and accompanied by an anisotropic expansion in the orthogonal ac plane at the transition point.


Model studies on segmental movement in lumbar spine using a semi-automated program for volume fusion.
To validate a new non-invasive CT method for measuring segmental translations in lumbar spine in a phantom using plastic vertebrae with tantalum markers and human vertebrae. One hundred and four CT volumes were acquired of a phantom incorporating three lumbar vertebrae. Lumbar segmental translation was simulated by altering the position of one vertebra in all three cardinal axes between acquisitions. The CT volumes were combined into 64 case pairs, simulating lumbar segmental movement of up to 3 mm between acquisitions. The relative movement between the vertebrae was evaluated visually and numerically using a volume fusion image post-processing tool. Results were correlated to direct measurements of the phantom. On visual inspection, translation of at least 1 mm or more could be safely detected and correlated with separation between the vertebrae in three dimensions. There were no significant differences between plastic and human vertebrae. Numerically, the accuracy limit for all the CT measurements of the 3D segmental translations was 0.56 mm (median: 0.12; range: -0.76 to +0.49 mm). The accuracy for the sagittal axis was 0.45 mm (median: 0.10; range: -0.46 to +0.62 mm); the accuracy for the coronal axis was 0.46 mm (median: 0.09; range: -0.66 to +0.69 mm); and the accuracy for the axial axis was 0.45 mm (median: 0.05; range: -0.72 to + 0.62 mm). The repeatability, calculated over 10 cases, was 0.35 mm (median: 0.16; range: -0.26 to +0.30 mm). The accuracy of this non-invasive method is better than that of current routine methods for detecting segmental movements. The method allows both visual and numerical evaluation of such movements. Further studies are needed to validate this method in patients.


Behavioral and social interventions to promote optimal HIV prevention and care continua outcomes in the United States.
This review reports on trends in behavioral and social intervention research in the United States published over the past year (2020-2021) investigating HIV prevention and care outcomes, organized by the level of intervention focus - individual, dyadic, and organizational. Researchers have continued to develop and evaluate behavioral and social interventions to reduce HIV acquisition risk and disease progression. With few exceptions, social and behavioral interventions have primarily focused on individuals as the unit of behavior change. Interventions operating at the individual-, dyadic-, and organizational-level have made strides to reduce HIV transmission risk and disease progressing by addressing mental health, substance use, stigma, peer and romantic relationships, and, to some extent, structural vulnerabilities. Social and behavioral interventions continue to be critical in addressing HIV inequities in the United States. An important gap in the literature is the need for multilevel interventions designed and implemented within existing community-based organizations and local healthcare settings. We call on researchers to continue to attend to the structural, environmental, and economic vulnerabilities that shape HIV inequities in the development of multilevel approaches necessary to realize the full potential of existing and emerging HIV prevention and care strategies.


The heart and diabetes. Vascular and metabolic aspects.
The metabolic changes in the heart--increased glycogen, triglycerides, and cyclic AMP, and decreased ATP and creatine phosphate--indicate that diabetes is a generalized disorder of cellular metabolism. The summarized observations provide additional biochemical reasons for early detection and treatment of patients with diabetes mellitus. Cognizance of three metabolic events are relevant to the treatment of the diabetic patient during acute cardiac events such as myocardial infarction.


Alkaloid profiling of herbal drugs using high resolution mass spectrometry.
Herbal infusions are consumed worldwide thanks to their "natural" beneficial effects, also due to the presence of alkaloids, although these compounds can have poisonous effects. A method combining online solid-phase purification with high resolution mass spectrometry was used to define the alkaloid profiles of 117 herbs and 7 commercial blends. Forty-one alkaloids were quantified in reference to analytical standards, while the presence of a further 116 was confirmed based on accurate mass, retention time, and fragmentation profile. The targeted study showed that 52% of herbs and 42% of commercial blends contained at least one alkaloid. Pyrrolizidines were the most commonly present (26% of samples), with concentrations generally ranging from the quantification limit to roughly 100 μg kg-1 . Moreover, a homemade infusion was studied, finding on average 45% and 6% lower extraction for pyrrolizidine and steroidal alkaloids, respectively. Nevertheless, the migration of pyrrolizidines was confirmed. The study confirmed the frequent presence, natural or accidental, of alkaloids in commercial infusion herbs, highlighting the urgent need for routine and accurate controls.


Extended lactations in a seasonal-calving pastoral system of production to modulate the effects of reproductive failure.
This study was conducted to determine whether extending the calving interval (CI) to 24 mo would be an alternative to culling and replacing cows that had failed to become pregnant. Forty-six nonpregnant lactating cows were assembled in November 2004 and assigned to receive either 3kg (low) or 6kg (high) of concentrate supplement and a basal diet of grass silage and maize silage over the winter period (13 wk). Cows returned to pasture in late March and received 1kg of concentrate/d until dry-off (milk yield <5 kg/d). Cumulative milk production was calculated from calving to the end of November 2004 (12-mo CI) and from the start of December 2004 until dry off in 2005 (extended lactation part of 24-mo CI). High winter feeding resulted in greater milk production over the winter confinement (20.0+/-0.3 vs. 17.8+/-0.3 kg/d for high and low winter feeding, respectively) and had a carryover effect during the remainder of the 24-mo CI period (5,177 vs. 4,686kg; SEM=173kg). At the end of the study, cows were ranked on cumulative milk solids and separated into 3 groups (R1, R2, and R3). During the 24-mo CI, milk yields were 7,287, 6,267, and 5,273kg (SEM=308kg) in yr 1, and 5,738, 4,836, and 4,266 (SEM=241kg) in yr 2 for R1, R2, and R3, respectively. Eighty-five percent of the cows became pregnant during the breeding season of yr 2, with a conception rate to first service of 52%. An economic analysis of different ranks with a 12-mo CI, a 24-mo CI, and an annualized herd effect, which compared an efficient spring calving system with 30% recycled cows in R1 and 10% recycled cows in R3, was carried out. Farm profit was reduced by 60% and 65% at a milk price of 22.3 euro-cents (c)/L with the corresponding values of 17% and 30% for a milk price of 30 c/L, respectively, when R1 and R3 systems were compared with an efficient spring milk (12-mo CI) production system. Within a spring system where 30% and 10% of R1 and R3 animals were subjected to extended lactations, the profit difference was reduced compared with an efficient spring system, The results indicated that lactations with a 24-mo CI may be a viable alternative to culling nonpregnant cows and be economically more suited to higher producing cows.


Effects of phosphated titanium and enamel matrix derivatives on osteoblast behavior in vitro.
The purpose of this study was to evaluate the effects of phosphated titanium and enamel matrix derivatives (EMD) on osteoblast function. Primary rat osteoblasts were cultured on disks of either phosphated or nonphosphated titanium. In half of the samples 180 microg of EMD was immediately added. The medium was changed every 2 days for 28 days and then analyzed using transforming growth factor-beta1 (TGF-beta1) and interleukin-1beta (IL-1beta) enzyme-linked immunosorbent assays (ELISAs). Scanning electron microscopy and light microscopy were used to evaluate nodule formation and mineralization. Microscopic evaluation revealed no differences in osteoblast attachment between the 4 groups. Osteoblast nodule formation was observed in all groups. In the absence of mineralizing media, nodules on the nonphosphated titanium samples showed no evidence of mineralization. All nodules on the phosphated titanium had evidence of mineralization. ELISA revealed no significant differences in IL-1beta production between any of the groups. The EMD-treated osteoblasts produced significantly more TGF-beta1 than non-EMD-treated cells for up to 8 days, and osteoblasts on phosphated titanium produced significantly more TGF-beta1 at 8 days. Osteoblast attachment appeared unaffected by surface treatment. EMD initiated early TGF-beta1 production, but production decreased to control levels within 10 days. Phosphated titanium increased TGF-beta1 production at 8 days and induced nodule mineralization even in the absence of mineralizing medium.


[Autophagy Does Not Contribute to TKI Response in a Imatinib-resistant Chronic Myeloid Leukemia Cell Line].
Autophagy is an evolutionarily conserved cellular process in which components of the cytoplasm are delivered to lysosomes for degradation and has been proposed to play a role in imatinib resistance in chronic myeloid leukemia cells. Chronic myeloid leukemia is a clonal myeloproliferative disorder arising from the neoplastic transformation of the hematopoietic stem cell. We used a Bcr-Abl-independent and imatinib-resistant K562 subpopulation (K562-IR) that we generated earlier in our laboratory for this study. We showed that in the presence of imatinib autophagy was triggered via LC3I/II transformation, p62 protein expression and acidic vacuoles accumulation in tyrosine kinase inhibitor-sensitive K562 cells; whereas in the cell line K562-IR which is imatinib-resistant and Bcr-Abl independent, autophagy is not triggered. With ongoing research and trails to combine tyrosine kinase inhibitors with autophagy inhibitors, our results suggest a model of resistance in which treatment with a TKI inhibitor does not increase autophagy, basically because its presence does not cause cellular stress due to Bcr-Abl signaling not being required for survival.


A new insight into the oscillation characteristics of endosonic files used in dentistry.
The aim of this study was to assess the oscillation characteristics of unconstrained endosonic files using a scanning laser vibrometer (SLV). Factors investigated included file vibration frequency and node/antinode location as well as the variation in file displacement amplitude due to increasing generator power setting. A 30 kHz Mini Piezon generator (Electro-Medical Systems, Switzerland) was used in conjunction with a #15 and #35 K-file. Each file was fixed in position with the long axis of the file perpendicular to the SLV camera head. The laser from the SLV was scanned over the length of the oscillating file for generator power settings 1 to 5 (minimum to half power). Measurements were repeated ten times. The fundamental vibration frequency for both files was 27.50 kHz. Scans of each file showed the positions of nodes/anti-nodes along the file length. The #15 file demonstrated no significant variation in its mean maximum displacement amplitude with increasing generator power, except at power setting 5, where a decrease in displacement amplitude was observed. The #35 file showed a general increase in mean maximum displacement amplitude with increasing power setting, except at power setting 4 where a 65% decrease in displacement amplitude occurred. In conclusion, scanning laser vibrometry is an effective method for assessing endosonic file vibration characteristics. The SLV was able to demonstrate that (unloaded) file vibration displacement amplitude does not increase linearly with increasing generator power. Further work is being performed on a greater variety of files and generators. Vibration characteristics of files under various loads and varying degrees of constraint should also be investigated.


Miscibility behavior of sphingomyelin with phytosterol derivatives by a Langmuir monolayer approach.
The miscibility behavior of palmitoyl sphingomyelin (PSM) with phytosterol derivatives of β-sitosterol (SITO), β-sitosteryl glucoside (SG), and β-sitosteryl glucoside palmitate (SGP) was systematically investigated using Langmuir monolayers. The surface pressure (π)-molecular area (A) and surface potential (ΔV)-A isotherms for binary PSM/SITO, PSM/SG, and PSM/SGP systems on 0.02 M Tris buffer with 0.13 M NaCl (pH 7.4) were measured as a function of the molar fraction of PSM (X(PSM)). The surface potentials (ΔV) of the pure components were analyzed using the three-layer model proposed by Demchak and Fort [J. Colloid Interface Sci. 46 (1974) 191-203]. The contributions of the hydrophilic D-glucose moiety, hydrophobic palmitoyl group, and sphingomyelin group to the vertical component of the dipole moment (μ(⊥)) were evaluated. The thermodynamic quantities, based on the π-A isotherms, revealed that PSM interacts attractively with all three phytosterol derivatives in the following order: SITO > SGP > SG. In addition, the two-dimensional phase diagram constructed based on the phase transition pressure (π(eq)), from a liquid-expanded to liquid-condensed state, and collapse (π(c)) pressure shows that the two-component systems are all miscible with each other. The manner of miscibility between PSM/SG and PSM/SGP systems is found to be opposite in the large X(PSM) region. The interaction between the same molecules (PSM-PSM or SG-SG) is stronger than that of the different molecules (PSM-SG) in the PSM/SG system, and vice versa in the PSM/SGP system. These results suggest that the incorporation of a D-glucose and palmitoyl group to a SITO molecule dramatically changes the miscibility behavior with PSM. Observations using fluorescence microscopy imaging also provide insights into miscibility behavior in the monolayer state.


Risk of benign gynaecological diseases and hormonal disorders according to responsiveness to ovarian stimulation in IVF: a follow-up study of 8714 women.
Over the past decade, attention has been focused increasingly on the long-term health effects of IVF in women. Assuming that hormonal changes due to stimulation regimens for IVF are strongest among 'high' responders, we evaluated whether responsiveness to ovarian stimulation in IVF is predictive of the risk of benign gynaecological disorders >12 months after the last IVF cycle. A nationwide historical cohort study of women who underwent IVF treatment was conducted. After a median time of 4.6 years following the last IVF treatment cycle, 8714 cohort members completed a health survey questionnaire that inquired about reproductive variables and the occurrence and age at onset of specific medical conditions including uterine leiomyoma, surgically removed ovarian cysts and thyroid disorders. Detailed data on cause of subfertility and IVF treatment were collected from the medical records. Women were included in the 'high responders' group when on average >/=14 oocytes were retrieved per IVF cycle (n = 1562), in the 'normal responders' group when they had a mean number of 4-13 retrieved oocytes (n = 6033), and in the 'low responders' group when they had a mean number of 0-3 retrieved oocytes per cycle (n = 1119). Among women with a high response to ovarian stimulation, we found a borderline significantly decreased risk of uterine leiomyoma [relative risk (RR) = 0.6; 95% confidence interval (CI) 0.4-1.0] and surgically removed ovarian cysts (RR = 0.6; 95% CI 0.3-1.0) in comparison with 'normal responders'. After OHSS, the age-adjusted RRs were 1.8 (95% CI 0.9-3.8) for having surgically removed ovarian cysts and 1.0 (95% CI 0.4-2.2) for uterine leiomyoma (both not significant). Despite the small number of events observed, highly elevated risks of gynaecological disorders and hormonal diseases in women undergoing IVF treatment can be excluded based on the present data and this follow-up period. Women with a low response to ovarian stimulation tended to have higher risks of benign gynaecological diseases than high responders.


Estrogens reduce and withdrawal of estrogens increase risk of microsatellite instability-positive colon cancer.
There are sex differences in the occurrence of microsatellite instability (MSI) in colon tumors. Taken together with the epidemiological evidence that hormone replacement therapy (HRT) and, less consistently, parity, are inversely associated with colon cancer, it has been hypothesized that estrogens are associated with MSI. The purpose of this study was to evaluate sex-specific differences in the prevalence of MSI in colon tumors and to determine whether reproductive history and hormonal exposures are associated with MSI. Using data from a population-based case-control study of 1836 cases with MSI data and 2410 population-based controls, we evaluated sex, reproductive factors, and hormone exposure in relation to the presence or absence of MSI in tumors. MSI was evaluated by a panel of 10 tetranucleotide repeats, the noncoding mononucleotide repeat BAT-26, and the coding mononucleotide repeat in transforming growth factor beta receptor type II (TGFbetaRII). Exposure data on reproduction, hormone use, obesity, and physical activity were obtained from an interviewer-administered questionnaire. Women were less likely then men to have MSI+ tumors at a young age and more likely to have unstable tumors at an older age; we observed a significant interaction (P < 0.01) between age, sex, and MSI. Evaluation of reproductive factors showed that women who had ever been pregnant had half the risk of MSI+ tumors compared with women who had never been pregnant. In complementary fashion, total ovulatory months were associated with an increased risk of MSI+ tumors [odds ratio (OR), 2.1; 95% confidence interval (CI), 1.1-4.0 comparing MSI+ versus MSI- tumors]. Age at first and last pregnancy did not influence the association. The observed associations were strongest among women <60 years of age at the time of diagnosis. Having used oral contraceptives was associated with a lower risk of MSI+ tumors (OR, 0.7; 95% CI, 0.4-1.2); recent users of HRT were at a reduced risk of MSI+ tumors (OR, 0.8; 95% CI, 0.5-1.4); and women who were former HRT users were at an increased risk of MSI+ tumors (OR, 1.8; 95% CI, 1.1-3.0). Obesity and lack of physical activity were associated with an elevated risk of both MSI+ (OR, 1.7; 95% CI, 0.7-3.3) and MSI- (OR, 2.2; 95% CI, 1.7-3.) tumors in men, but only with MSI- (OR, 1.5; 95% CI, 1.1-2.2) tumors in women. The excess of MSI+ tumors in women is explained by the excess of MSI+ tumors at older ages. Our data suggest that estrogen exposure in women protects against MSI, whereas the lack of estrogen in older women increases risk of instability. HRT in these older women may, again, reduce the risk of unstable tumors. A model for the way in which estrogens (endogenous, exogenous, and obesity-associated) modify the risk of MSI+ tumors is proposed.


Dihydrotanshinone I inhibits the growth of hepatoma cells by direct inhibition of Src.
Liver cancer is one of the leading causes of cancer-related death worldwide. Dihydrotanshinone I (DHI) was shown to inhibit the growth of several types of cancer. However, research related to hepatoma treatment using DHI is limited. Here, we explored the inhibitory effect of DHI on the growth of hepatoma cells, and investigated the underlying molecular mechanisms. The proliferation of Hep3B, SMCC-7721 and SK-Hep1 hepatoma cells was evaluated using the MTS and Edu staining assay. Hepatoma cell death was analyzed with a LIVE/DEAD Cell Imaging Kit. The relative expression and phosphorylation of proto-oncogene tyrosine-protein kinase Src (Src) and signal transducer and activator of transcription-3 (STAT3) proteins in hepatoma cells, as well as the expression of other protein components, were measured by western blotting. The structural interaction of DHI with Src proteins was evaluated by molecular docking, molecular dynamics simulation, surface plasmon resonance imaging and Src kinase inhibition assay. Src overexpression was achieved by infection with an adenovirus vector encoding human Src. Subsequently, the effects of DHI on tumor growth inhibition were further validated using mouse xenograft models of hepatoma. In vitro studies showed that treatment with DHI inhibited the proliferation and promoted cell death of Hep3B, SMCC-7721 and SK-Hep1 hepatoma cells. We further identified and verified Src as a direct target of DHI by using molecular stimulation, surface plasmon resonance image and Src kinase inhibition assay. Treatment with DHI reduced the in vitro phosphorylation levels of Src and STAT3, a transcription factor regulated by Src. In the xenograft mouse models, DHI dose-dependently suppressed tumor growth and Src and STAT3 phosphorylation. Moreover, Src overexpression partly abrogated the inhibitory effects of DHI on the proliferation and cell death in hepatoma cells. Our results suggest that DHI inhibits the growth of hepatoma cells by direct inhibition of Src.


Intestinal ultrastructure after prolonged use of an elemental diet.
The role of 3 diets (Purina, whole casein and hydrolyzed casein) on the morphological aspect of the intestinal mucosa has been studied in adult mice, irradiated with a single dose of 950 R or with 4 doses of 600 R. The experimental group receiving the hydrolyzed casein exhibited always the fastest recovery. 45 days after a single irradiation, some alterations of columnar cells were still noted in the other groups. The prolonged use of an hydrolyzed casein (6 months) did not alter the structure of the mucosal cells.


Functional recovery following surgery for chronic subdural hematoma.
Among the elderly, chronic subdural hematoma is a relatively common neurosurgical condition. Presenting symptoms range from headache and focal neurological deficits to seizure and coma depending on location and extent of brain compression. Functional recovery following surgery for chronic subdural hematoma is central to quality of life and ongoing health for elderly patients; however, there is a paucity of data regarding functional recovery in this population. In this study, the physical activity of patients who underwent surgical evacuation of chronic subdural hematoma was surveyed, as well as participation in physical therapy following surgery. In total, 38 patients completed the survey. Of the 30 patients who exercised regularly before surgery, 28 (90.3%) returned to exercise within 1 year after surgery. Of 13 patients who reported playing hobby sports before surgery, 9 (69.2%) returned to those sports. 17/38 (44.7%) patients participated in physical therapy after surgery. 35/38 (92.1%) of patients reported that the surgery improved their quality of life. The majority of patients who underwent surgery for chronic subdural hematoma were able to return to exercise within 1 year. Participation in physical therapy was associated with return to exercise and sports. Further study is needed to determine which factors contribute to a return to baseline levels of physical activity following surgery for chronic subdural hematoma.


Astrocyte-specific but not neuron-specific transmembrane TNF triggers inflammation and degeneration in the central nervous system of transgenic mice.
To study the involvement of TNF in cerebral pathology in vivo and to define cellular interactions within the central nervous system (CNS) that promote TNF signaling, we have expressed this cytokine either as a wild-type or a mutant transmembrane form in astrocytes or neurons of transgenic mice. Mice expressing wild-type human TNF in either of these cell types spontaneously develop a neurologic disorder manifested by ataxia, seizures, and paralysis and bear histologic evidence of chronic CNS inflammation and degeneration. Moreover, astrocyte-specific expression of transmembrane TNF triggers a similar neurologic phenotype. Interestingly, transgenic mice producing a high level of transmembrane TNF in their neurons develop no apparent phenotypic abnormalities, suggesting that appropriate cellular interactions should form to allow for contact-dependent TNF signals to induce CNS pathology. These results demonstrate that target cells mediating the neuroinflammatory activities of TNF localize in the vicinity of astrocytes rather than neurons.


[Value of exercise electrocardiography and other current instrumental studies in the evaluation of percutaneous coronary interventions and in the detection of restenosis].
The current instrumental studies (graded exercise echocardiography (ECG)), exercise tests in combination with myocardial imaging (echocardiography, myocardial perfusion scintigraphy) used to evaluate restenosis after percutaneous coronary interventions (PCI) in patients with coronary heart disease are considered. The sensitivity, specificity, and prognostic value of these studies versus coronarography in the diagnosis of restenosis after PCI are given. The capabilities of other diagnostic techniques (ultrasound study of brachial artery dysfunction, intravascular ultrasound study of coronary arteries, multispiral computed tomography, etc.) are analyzed. It is emphasized that periodic use of exercise ECG tests after PCI has no advantages over their performance only on the basis of the clinical findings of the impact on quality of life, functional status, and clinical signs.


Management of clinically non-functioning pituitary adenoma.
Clinically NFPA is currently the preferred term for designing all the pituitary adenomas which are not hormonally active (in other words, not associated with clinical syndromes such as amenorrhea-galactorrhea in the context of prolactinomas, acromegaly, Cushing's disease or hyperthyroidism secondary to TSH-secreting adenomas). They account for 15-30% of pituitary adenomas. Diagnosis is usually made either in the context of mass effect due to a macroadenoma or, increasingly, fortuitously during imaging performed for some unrelated purpose; the latter case is known as pituitary incidentaloma. Surgery is indisputably indicated in case of tumoral syndrome, but other aspects of NFPA (hormonal work-up, follow-up, and especially postoperative follow-up, management of remnant or recurrence, the special case of incidentaloma, or apoplexy) remain controversial. The French Endocrinology Society (SFE) therefore set up an expert working group of endocrinologists, neurosurgeons, ophthalmologists, neuroradiologists, pathologists and biologists to draw up guidelines, at the 2012 SFE Congress in Toulouse, France. The present article presents the guidelines suggested by this group of French-speaking experts.